MiR-541 is Associated with the Prognosis of Liver Cirrhosis and Directly Targets JAG2 to Inhibit the Activation of Hepatic Stellate Cells

Overview

Journal BMC Gastroenterol

Publisher Biomed Central

Specialty Gastroenterology

Date 2024 Feb 23

PMID 38395762

Authors

Jin-Pei Liu

Shao-Hua Song

Pei-Mei Shi

Xiao-Yu Qin

Bai-Nan Zheng

Shu-Qing Liu

Chen-Hong Ding

Xin Zhang

Wei-Fen Xie

Yi-Hai Shi

Wen-Ping Xu

Affiliations

Soon will be listed here.

Abstract

Background: The activation of hepatic stellate cells (HSCs) has been emphasized as a leading event of the pathogenesis of liver cirrhosis, while the exact mechanism of its activation is largely unknown. Furthermore, the novel non-invasive predictors of prognosis in cirrhotic patients warrant more exploration. miR-541 has been identified as a tumor suppressor in hepatocellular carcinoma and a regulator of fibrotic disease, such as lung fibrosis and renal fibrosis. However, its role in liver cirrhosis has not been reported.

Methods: Real-time PCR was used to detect miR-541 expression in the liver tissues and sera of liver cirrhosis patients and in the human LX-2. Gain- and loss-of-function assays were performed to evaluate the effects of miR-541 on the activation of LX-2. Bioinformatics analysis and a luciferase reporter assay were conducted to investigate the target gene of miR-541.

Results: miR-541 was downregulated in the tissues and sera of patients with liver cirrhosis, which was exacerbated by deteriorating disease severity. Importantly, the lower expression of miR-541 was associated with more episodes of complications including ascites and hepatic encephalopathy, a shorter overall lifespan, and decompensation-free survival. Moreover, multivariate Cox's regression analysis verified lower serum miR-541 as an independent risk factor for liver-related death in cirrhotic patients (HR = 0.394; 95% CI: 0.164-0.947; P = 0.037). miR-541 was also decreased in LX-2 cells activated by TGF-β and the overexpression of miR-541 inhibited the proliferation, activation and hydroxyproline secretion of LX-2 cells. JAG2 is an important ligand of Notch signaling and was identified as a direct target gene of miR-541. The expression of JAG2 was upregulated in the liver tissues of cirrhotic patients and was inversely correlated with miR-541 levels. A rescue assay further confirmed that JAG2 was involved in the function of miR-541 when regulating LX-2 activation and Notch signaling.

Conclusions: Dysregulation of miR-541/JAG2 axis might be a as a new mechanism of liver fibrosis, and miR-541 could serve as a novel non-invasive biomarker and therapeutic targets for liver cirrhosis.

References

Kisseleva T, Brenner D . Molecular and cellular mechanisms of liver fibrosis and its regression. Nat Rev Gastroenterol Hepatol. 2020; 18(3):151-166. DOI: 10.1038/s41575-020-00372-7. View

Ren S, Chen J, Wang Q, Li X, Xu Y, Zhang X . MicroRNA-744/transforming growth factor β1 relationship regulates liver cirrhosis. Hepatol Int. 2019; 13(6):814-825. PMC: 7400990. DOI: 10.1007/s12072-019-09993-w. View

Innes H, Morling J, Buch S, Hamill V, Stickel F, Guha I . Performance of routine risk scores for predicting cirrhosis-related morbidity in the community. J Hepatol. 2022; 77(2):365-376. DOI: 10.1016/j.jhep.2022.02.022. View

Wang X, He Y, Mackowiak B, Gao B . MicroRNAs as regulators, biomarkers and therapeutic targets in liver diseases. Gut. 2020; 70(4):784-795. DOI: 10.1136/gutjnl-2020-322526. View

Xu Q, Zhou L, Yang G, Meng F, Wan Y, Wang L . CircIL4R facilitates the tumorigenesis and inhibits ferroptosis in hepatocellular carcinoma by regulating the miR-541-3p/GPX4 axis. Cell Biol Int. 2020; 44(11):2344-2356. DOI: 10.1002/cbin.11444. View

Benetatos L, Hatzimichael E, Londin E, Vartholomatos G, Loher P, Rigoutsos I . The microRNAs within the DLK1-DIO3 genomic region: involvement in disease pathogenesis. Cell Mol Life Sci. 2012; 70(5):795-814. PMC: 11114045. DOI: 10.1007/s00018-012-1080-8. View

Reynolds S, Hill C, Alsudayri A, Lallier S, Wijeratne S, Tan Z . Assemblies of JAG1 and JAG2 determine tracheobronchial cell fate in mucosecretory lung disease. JCI Insight. 2022; 7(15). PMC: 9462471. DOI: 10.1172/jci.insight.157380. View

DAmico G, Garcia-Tsao G, Pagliaro L . Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol. 2005; 44(1):217-31. DOI: 10.1016/j.jhep.2005.10.013. View

Peng Y, Qi X, Guo X . Child-Pugh Versus MELD Score for the Assessment of Prognosis in Liver Cirrhosis: A Systematic Review and Meta-Analysis of Observational Studies. Medicine (Baltimore). 2016; 95(8):e2877. PMC: 4779019. DOI: 10.1097/MD.0000000000002877. View

10.

Liang X, Yan Z, Wang P, Liu Y, Ao X, Liu Z . Irradiation Activates MZF1 to Inhibit miR-541-5p Expression and Promote Epithelial-Mesenchymal Transition (EMT) in Radiation-Induced Pulmonary Fibrosis (RIPF) by Upregulating Slug. Int J Mol Sci. 2021; 22(21). PMC: 8582843. DOI: 10.3390/ijms222111309. View

11.

Gines P, Krag A, Abraldes J, Sola E, Fabrellas N, Kamath P . Liver cirrhosis. Lancet. 2021; 398(10308):1359-1376. DOI: 10.1016/S0140-6736(21)01374-X. View

12.

Chen Y, Gao D, Huang L . In vivo delivery of miRNAs for cancer therapy: challenges and strategies. Adv Drug Deliv Rev. 2014; 81:128-41. PMC: 5009470. DOI: 10.1016/j.addr.2014.05.009. View

13.

Yang J, Tao H, Liu L, Hu W, Deng Z, Li J . miR-200a controls hepatic stellate cell activation and fibrosis via SIRT1/Notch1 signal pathway. Inflamm Res. 2016; 66(4):341-352. DOI: 10.1007/s00011-016-1020-4. View

14.

Shen J, Yan J, Wang Q, Zhuang L, Luo Y . MicroRNA-541-5p REgulates Type II Alveolar Epithelial Cell Proliferation and Activity by Modulating the HMGB1 Expression. Shock. 2022; 57(4):536-543. PMC: 8906253. DOI: 10.1097/SHK.0000000000001852. View

15.

Zaccherini G, Tufoni M, Iannone G, Caraceni P . Management of Ascites in Patients with Cirrhosis: An Update. J Clin Med. 2021; 10(22). PMC: 8621554. DOI: 10.3390/jcm10225226. View

16.

He Z, Shen F, Qi P, Zhai Z, Wang Z . miR-541-3p enhances the radiosensitivity of prostate cancer cells by inhibiting HSP27 expression and downregulating β-catenin. Cell Death Discov. 2021; 7(1):18. PMC: 7813831. DOI: 10.1038/s41420-020-00387-8. View

17.

Schwentner R, Jug G, Kauer M, Schnoller T, Waidhofer-Sollner P, Holter W . JAG2 signaling induces differentiation of CD14 monocytes into Langerhans cell histiocytosis-like cells. J Leukoc Biol. 2018; 105(1):101-111. DOI: 10.1002/JLB.1A0318-098R. View

18.

Ma Y, Yuan X, Han M, Xu Y, Han K, Liang P . miR-98-5p as a novel biomarker suppress liver fibrosis by targeting TGFβ receptor 1. Hepatol Int. 2022; 16(3):614-626. DOI: 10.1007/s12072-021-10277-5. View

19.

DAmico G, Morabito A, DAmico M, Pasta L, Malizia G, Rebora P . New concepts on the clinical course and stratification of compensated and decompensated cirrhosis. Hepatol Int. 2017; 12(Suppl 1):34-43. DOI: 10.1007/s12072-017-9808-z. View

20.

Li B, Wang L, Qi X, Liu Y, Li J, Lv J . NOTCH signaling inhibition after DAPT treatment exacerbates alveolar echinococcosis hepatic fibrosis by blocking M1 and enhancing M2 polarization. FASEB J. 2023; 37(5):e22901. DOI: 10.1096/fj.202202033R. View